Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases

• ClinicalTrials.gov Identifier: NCT03550391
• Recruitment Status: Recruiting
• First Posted: June 8, 2018
• Last Update Posted: May 14, 2024
• Sponsor: Canadian Cancer Trials Group
• Collaborators: Alliance for Clinical Trials in Oncology; NRG Oncology
• Information provided by (Responsible Party): Canadian Cancer Trials Group

Tracking Information

• First Submitted Date: April 30, 2018
• First Posted Date: June 8, 2018
• Last Update Posted Date: May 14, 2024
• Actual Study Start Date: November 22, 2018
• Estimated Primary Completion Date: June 30, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 22, 2021)

• Overall Survival [ Time Frame: 4.5 years ]
  To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine
• Neurocognitive progression-free survival [ Time Frame: 4.5 years ]
  To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine

Original Primary Outcome Measures (submitted: June 6, 2018)

• Overall Survival [ Time Frame: 3.5 years ]
  To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT
• Neurocognitive progression-free survival [ Time Frame: 3.5 years ]
  To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT

Current Secondary Outcome Measures (submitted: February 22, 2021)

• Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine [ Time Frame: 4.5 years ]
• Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine [ Time Frame: 4.5 years ]
• Number of salvage procedures following SRS in comparison to HA-WBRT + memantine [ Time Frame: 4.5 years ]
• Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine [ Time Frame: 4.5 years ]
  measured from date the patient is randomized to date at which there is a drop of at least 1.5 standard deviations from baseline in two of the six neurocognitive tests (all tests are standardized based on published norms)
• Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. [ Time Frame: 4.5 years ]
• Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine [ Time Frame: 4.5 years ]
• Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS [ Time Frame: 4.5 years ]
  a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery
• Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine. [ Time Frame: 4.5 years ]
  Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)
• Quality of life, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) with brain cancer module (BN20) [ Time Frame: 4.5 years ]
• Quality of life assessed by ECOG performance status [ Time Frame: 4.5 years ]
• Quality of life, as assessed by EQ-5D-5L [ Time Frame: 4.5 years ]
• Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases. [ Time Frame: 4.5 years ]
• Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes [ Time Frame: 4.5 years ]
• Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis [ Time Frame: 4.5 years ]
• Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes [ Time Frame: 4.5 years ]

Original Secondary Outcome Measures (submitted: June 6, 2018)

• Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive WBRT [ Time Frame: 3.5 years ]
• Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive WBRT [ Time Frame: 3.5 years ]
• Number of salvage procedures following SRS in comparison to WBRT [ Time Frame: 3.5 years ]
• Neurocognitive progression-free survival in patients who receive SRS compared to WBRT [ Time Frame: 3.5 years ]
  measured from date the patient is randomized to date at which there is a drop of at least 1.5 standard deviations from baseline in two of the six neurocognitive tests (all tests are standardized based on published norms)
• Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. [ Time Frame: 3.5 years ]
• Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to WBRT [ Time Frame: 3.5 years ]
• Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS [ Time Frame: 3.5 years ]
  a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery
• Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive WBRT. [ Time Frame: 3.5 years ]
  Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)
• Quality of life, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) with brain cancer module (BN20) [ Time Frame: 3.5 years ]
• Quality of life assessed by ECOG performance status [ Time Frame: 3.5 years ]
• Quality of life, as assessed by EQ-5D [ Time Frame: 3.5 years ]
• Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases. [ Time Frame: 3.5 years ]
• Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes [ Time Frame: 3.5 years ]
• Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis [ Time Frame: 3.5 years ]
• Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes [ Time Frame: 3.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases
• Official Title: A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases

Brief Summary

Stereotactic radiosurgery (SRS) is a commonly used treatment for brain tumors. It is a one-day (or in some cases two day), out-patient procedure during which a high dose of radiation is delivered to small spots in the brain while excluding the surrounding normal brain.

Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) is when radiation therapy is given to the whole brain, while trying to decrease the amount of radiation that is delivered to the area of the hippocampus. The hippocampus is a brain structure that is important for memory. Memantine is a drug that is given to help relieve symptoms that can be caused by WBRT, including problems with memory and other mental symptoms.

Health Canada, the regulatory body that oversees the use of drugs in Canada, has not approved the sale or use of memantine in combination with WBRT to treat this kind of cancer, although they have allowed its use in this study.

Detailed Description

The purpose of this research study is to compare the effects (good or bad) of receiving stereotactic radiosurgery (SRS) versus receiving hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus a drug called memantine, on brain metastases. Receiving SRS could control cancer that has spread to the brain.

This study will allow the researchers to know whether this different approach is better, the same, or worse than the usual approach. To decide if it is better, the study doctors will be looking to see if the stereotactic radiosurgery (SRS) helps to either slow the growth of cancer or stop it from coming back, compared to the usual approach. Doctors will also look to see if this new approach increases the life span of patients with this type of cancer, and if it helps with quality of life and cancer related symptoms.

The usual approach for patients who are not in a study is treatment with whole brain radiation therapy alone (WBRT).

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is an international multi-centre, open-label, randomized phase III trial comparing stereotactic radiosurgery compared with hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus memantine for 5-15 brain metastases

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Brain Metastases

Intervention

• Drug: Memantine
  20 mg (10 mg divided twice daily). Dose will be escalated by 5 mg per week. Memantine should start at 5 mg, and then increased in 5 mg increments at the following schedule, depending on the patient's response and tolerance:
• Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
  30Gy in 10 fractions
• Procedure: Stereotactic Radiosurgery (SRS)
  18-20 or 22 Gy in single fraction

Study Arms

• Experimental: Hippocampal-avoidant (HA-WBRT) plus Memantine
  WBRT 30Gy in 10 fractions + memantine
  Interventions:

  • Drug: Memantine
  • Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
• Experimental: Stereotactic Radiosurgery (SRS)
  SRS 18-20 or 22Gy in single fraction
  Intervention: Procedure: Stereotactic Radiosurgery (SRS)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 6, 2018): 206
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2027
• Estimated Primary Completion Date: June 30, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases).
• Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy.
• The largest brain metastasis must measure <2.5 cm in maximal diameter.
• Centre must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system.
• Patient must be > 18 years of age.
• Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance.
• ECOG performance status 0, 1, or 2.
• Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration.
• The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training.
• Facility is credentialed by IROC to perform SRS and HA-WBRT. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credintialing of this specific IMRT systems to be used in study patients for the purposes of HA-WBRT.
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate.
• A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures.
• Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment.
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.

Exclusion Criteria:

• Pregnant or nursing women.
• Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Inability to complete a brain MRI.
• Known allergy to gadolinium.
• Prior cranial radiation therapy.
• Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT.
• Primary germ cell tumour, small cell carcinoma, or lymphoma.
• Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells.
• A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve.
• Surgical resection of a brain metastasis (stereotactic biopsies will be allowed).
• More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI.
• Prior allergic reaction to memantine.
• Current alcohol or drug abuse.
• Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan.
• Diagnosis of chronic liver disease/cirrhosis of the liver (e.g. Child-Pugh class B or C).
• Patients with architectural distortion of lateral ventricular systems, which, in the opinion of the local investigator, makes hippocampal delineation challenging

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Chris O'Callaghan; 613-533-6430; cocallaghan@ctg.queensu.ca

• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT03550391
• Other Study ID Numbers: CCTG CE.7; NCI-2018-00395 ( Other Identifier: NCI CTRP )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Canadian Cancer Trials Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Canadian Cancer Trials Group
• Original Study Sponsor: Same as current

Collaborators

• Alliance for Clinical Trials in Oncology
• NRG Oncology

Investigators

• Study Chair: David Roberge; CHUM-Centre Hospitalier de l'Universite de Montreal
• Study Chair: Michael Chan; Wake Forest School of Medicine, Winston-Salem, NC
• Study Chair: Vina Gondi; Northwestern Medicine Cancer Center, Warrenville IL

• PRS Account: Canadian Cancer Trials Group
• Verification Date: March 2024